Water-dispersible tablets

ABSTRACT

A water-dispersible tablet comprising 2-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine together with a swellable clay disintegrating agent and a further disintegrating agent. The tablet can be used in the treatment of neurodegenerative and other neurological disorders of the central nervous system, the etiology of which includes excessive release of neurotransmitter glutamate, including Alzheimer&#39;s disease, cerebral ischemic damage, chronic pain and epilepsy.

The present invention relates to a water-dispersible tablet formulationcontaining4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine.

European Patent Specification No. 372934 discloses the compound4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)-pyrimidine(hereinafter referred to as "AMTP") and their use in the treatment ofneurodegenerative and other neurological disorders of the centralnervous system, the aetiology of which includes excessive release ofneurotransmitter glutamate, including Alzheimer's disease, cerebralischemic damage, chronic pain and epilepsy.

In order to be able to administer AMTP to patients to achieve theoptimum therapeutic benefit from the drug, it would be desirable topresent the drug in a pharmaceutical formulation that is capable ofrapid dispersion in water.

Following extensive research and investigation, we have now discovered atablet formulation for AMTP that is capable of rapid dispersion inwater.

According to one aspect of the present invention there is provided awater-dispersible tablet comprising within the granules of the tabletAMTP together with a pharmaceutically acceptable swellable claydisintegrating agent to provide a tablet which is capable of dispersingin water within a period of 3 minutes to provide a dispersion which iscapable of passing through a sieve screen with a mesh aperture of 710 μmin accordance with the test for dispersible tablets defined in theBritish Pharmacopoeia, 1988, Volume II, page 895 which disclosure isherein incorporated by reference.

According to a further aspect of the present invention there is provideda water-dispersible tablet comprising within the granules of the tabletAMTP together with a pharmaceutically acceptable swellable claydisintegrating agent and a further pharmaceutically acceptabledisintegrating agent to provide a tablet which is capable of dispersingin water within a period of 3 minutes to provide a dispersion which iscapable of passing through a sieve screen with a mesh aperture of 710 μmin accordance with the test for dispersible tablets defined in theBritish Pharmacopoeia, 1988, Volume II page 895 which disclosure isherein incorporated by reference.

The above-mentioned test for dispersion time is carried out using thefollowing apparatus and method:

Apparatus

(a) A rigid basket-rack assembly supporting six cylindrical glass tubes75.0 to 80.0 mm long, 21.5 mm in internal diameter and with a wallthickness of about 2 mm.

(b) A cylindrical disc for each tube, each 20.55 to 20.85 mm in diameterand 9.35 to 9.65 mm thick, made of transparent plastic with a relativedensity of 1.18 to 1.20, pierced with five holes, each 2 mm in diameter,one in the centre and the other four spaced equally on a circle ofradius 6 mm from the centre of the disc. Four equally spaced grooves arecut in the lateral surface of the disc in such a way that at the uppersurface of the disc they are 9.5 mm wide and 2.55 mm deep and at thelower surface 1.6 mm square.

(c) The tubes are held vertically by two superimposed transparentplastic plates 90 mm in diameter and 6 mm thick, perforated by six holeshaving the same diameter as the tubes. The holes are equidistant fromthe centre of the plate and are equally spaced from one another.Attached to the underside of the lower plate is a piece of woven gauzemade from stainless steel wire 0.635 mm in diameter and having nominalmesh apertures of 2.00 mm.

(d) The plates are held rigidly in position and 77.5 mm apart byvertical metal rods at the periphery and a metal rod is also fixed tothe centre of the upper plate to enable the assembly to be attached to amechanical device capable of raising and lowering it smoothly through adistance of 50 to 60 mm at a constant frequency of between 28 and 32cycles per minute.

(e) The assembly is suspended in the liquid medium in a suitable vessel,preferably a 1000-ml beaker. The volume of liquid is such that when theassembly is in the highest position the wire mesh is at least 15 mmbelow the surface of the liquid and when the assembly is in the lowestposition the wire mesh is at least 25 mm above the bottom of the beakerand the upper open ends of the tubes remain above the surface of theliquid.

(f) A suitable device maintains the temperature of the liquid at 19° C.to 21° C.

The design of the basket-rack assembly may be varied provided that thespecifications for the glass tubes and wire mesh are maintained.

Method

Introduce one tablet into each tube, optionally adding a disc to eachtube. Suspend the assembly in the beaker containing the specified liquidand operate the apparatus for a maximum period of three minutes. Removethe assembly from the liquid. The tablets pass the test if all six havedispersed within a period of three minutes.

The test for dispersion quality (i.e. uniformity of dispersion) iscarried out as follows:

Place two tablets in 100 ml of water and stir until completelydispersed. A smooth dispersion is produced which passes through a sievescreen with a nominal mesh aperture of 710 μm.

A tablet according to the invention, as well as being quicklydispersible in water, has the added advantage that it meets the BritishPharmacopoeia (B. P.) test for dispersible tablets in respect ofdispersion times and dispersion quality (i.e. passage through a 710 μmsieve).

Preferably the dispersion time of a tablet according to the invention isless than 2 minutes, more preferably less than 1.50 minutes and mostpreferably less than 1 minute.

A further advantage of the tablets according to invention is thatbecause a relatively fine dispersion is formed the tablet may have alower dissolution time and thus the drug may be absorbed into the bloodstream much faster. Furthermore the fast dispersion times and relativelyfine dispersions obtained with tablets according to the invention arealso advantageous for swallowable tablets. Thus tablets according to theinvention can be presented both for dispersion in water and also fordirectly swallowing. Those tablets according to the invention that areintended for swelling are preferably film-coated to aid swallowing. Suchfilm-coating however increases the dispersion time up to 5 minutesdetermined in accordance with the above-mentioned B. P. test.

According to a further feature of the present invention therefore weprovide a water-dispersible film-coated tablet comprising within thegranules of the tablet AMTP together with a pharmaceutically acceptableswellable clay to provide a film-coated tablet which is capable ofdispersing in water within a period of 5 minutes to provide a dispersionwhich is capable of passing through a sieve screen with a mesh apertureof 710 μm in accordance with the above-defined British Pharmacopoeiatest for dispersible tablets subject to the variation of the said periodspecified in the test from 3 minutes to 5 minutes.

According to yet a further feature of the present invention therefore weprovide a water-dispersible film-coated tablet comprising within thegranules of the tablet AMTP together with a pharmaceutically acceptableswellable clay and a further pharmaceutically acceptable disintegratingagent to provide a film-coated tablet which is capable of dispersing inwater within a period of 5 minutes to provide a dispersion which iscapable of passing through a sieve screen with a mesh aperture of 710 μmin accordance with the above-defined British Pharmacopoeia test fordispersible tablets subject to the variation of the said periodspecified in the test from 3 minutes to 5 minutes. The references hereinto tablets according to the invention include both film-coated andnon-film-coated tablets.

After the dispersion has passed through the 710 μm mesh screen, thereshould be substantially no residue, except fragments of undissolvedtablet coating or shell, remaining on the screen or adhering to thelower surface of the disc, if a disc optionally has been used; and ifany residue remains, it should consist of a soft mass having no palpablyfirm, unmoistened core.

The particle size distribution of dispersions obtained by dispersingtablets according to the invention is set out in the following tablewith the increasingly preferred values being quoted from left to right.

    ______________________________________                                        Particle BP                  More    Most                                     Size (μm)*                                                                          Standard  Preferably                                                                              Preferably                                                                            Preferably                               ______________________________________                                        <710     <100%     100%      100%    100%                                     <300     --        >50%      >70%    >80%                                     <200     --        --        >50%    >70%                                     <150     --        --        --      >50%                                     ______________________________________                                         *(equivalent spherical volume diameter)                                  

The term "swellable clay" as used herein includes layered clays (such assmectites), porous fibrous clay minerals, and synthetic clay materialsrelated in structure to layered clays and porous fibrous clays.

The term "layered clays" as used herein includes substantiallyhomogeneous layered clays and mixtures thereof, and interstratified ormixed layered clays. Substantially homogeneous layered clays includesthe smectite group for example dioctahedral and trioctahedral types.Examples of dioctahedral smectites are the montmorillonite group(montmorillonoids); magnesium and other (e.g. calcium) aluminiumsilicates such as Veegum in its various grades e.g. Veegum, Veegum HV,Veegum F, and Veegum WG); almasilate; fullers earth (e.g. Surreyfinest); American fullers earth; bentonite; beidellite; chetomontmorillonite, Wyoming montmorillonite, Utah montmorillonite; Tataliaand Chambers montmorillonites; and iron rich smectites such as nontrite(e.g. Garfield nontronite) and ferrian smectites.

Examples of trioctahedral smectites (also known as saponites) areSwinefordite, hectorite, stevensite. Examples of smectites containingmore unusual elements are Volkhonsite, Medmontite, Sauconite, nickelsmectites and vanadium smectites. As well as the montmorillonite group,related smectites such as vermiculites may also have application.

The term "interstratified or mixed layer clays", as used herein includesclays involving different layers arranged in a regular or irregularstructure. The most common examples of such clays have generally twocomponents in substantially equal proportions and have been givenmineral names such as rectorite (mica-smectite), hydrobiotite(biotite-vermiculite), corrensiten (chlorite-smectite) allettite(talc-saponite). More irregular arrangements include illite-smectite,chlorite-smectite, and kaolinite-smectite. Further examples ofinterstratified clays are tosudite, tarasovite, allevardite, Japanesebentonite ("acid clays"), AWAZU acid clay, and kaolinite-smectite. Othermixed layer clays may include one or more of the following minerals:clinchlore, chamosite, nimite, thuringite, sudoite, and cookeite. Mixedlayer smectities are also known e.g. interdispersed montmorillonite andbeidellite layers. The layers of mixed layer clays may be homogeneous ornon-homogeneous.

The term "porous fibrous clays" includes palygorskite and sepiolite suchas, for example attapulgite and American fuller's earth.

The term "synthetic clay materials" as used herein includes materialsrelated in structure to layered clays and porous fibrous clays such assynthetic hectorite (lithium magnesium sodium silicate) for examplelaponite^(R).

It will be appreciated that within the scope of the invention thefollowing classes of clays have application alone or in combination andin mixed layer clays: kaolinites, serpentines, pyrophyllites, talc,micas and brittle micas, chlorites, smectites and vermiculites,palygorskites and sepiolites. Other phyllosilicates (clay minerals)which may be employed in the tablets according to the invention areallophane and imogolite.

The following references describe the characterisation of clays of theabove types: Chemistry of Clay and Clay Minerals. Edited by A. C. D.Newman. Mineralogical Society Monograph No. 6, 1987, Chapter 1; S. W.Bailey; Summary of recommendations of AIPEA Nomenclature Committee, ClayMinerals 15, 85-93; and A Handbook of Determinative Methods inMineralogy, 1987, Chapter 1 by P. L. Hall.

Suitably the swellable clay is a pharmaceutically acceptable crystallinemineral clay having a lattice structure which expands upon hydration,preferably a pharmaceutically acceptable smectite or attapulgite clay,especially a montmorillonoid, more preferably yet a montmorillonoidchosen from the group consisting of montmorillonite, sauconite,vermiculite, bentonite and hectorite, still more preferably an aluminiummagnesium silicate (also termed magnesium aluminium silicates) and mostpreferably Veegum^(R). Veegum^(R) is a complex colloidal magnesiumaluminium silicate described and characterised in Technical Booklet No.97, R. T. Vanderbilt Company, Inc., Industrial Minerals and Chemicals,30 Winfield Street, Norwalk, Conn. 06855, U.S.A.: an especiallypreferred such material is Veegum F (loc. cit.).

The term "smectite" as used herein in relation to tablets of the presentinvention includes the smectites as exemplified herein and withreference to O'Brian P. and Williamson C. J., in "Clays and ClayMinerals vol. 38 No. 3 pp322-326, 1990" and the other clay nomenclaturereferences set out hereinbefore.

The term "magnesium aluminium silicate" as used herein in relation totablets of the present invention should be understood to include theAluminium Magnesium Silicate defined in the British Pharmacopoeia,volume 1, pages 27-28, 1988 and the Magnesium Aluminium Silicate definedin the United States Pharmacopoeia, National Formulary XVI, pages1943-1944, 1990. Advantageously, said silicate is in the form of amicrofine powder having a No. 325 U.S. Standard mesh particle size, aviscosity of 250 cps (±25%) for a 5.5% (w/v) aqueous dispersion and anacid demand (the volume in ml. of 0.1N hydrochloric acid required toreduce the pH of one gram to 4) of 6-8: such a material is available asVEEGUM F (R. T. Vanderbilt Co., New York, N.Y., U.S.A.; K & K-GreeffChemicals Ltd., Croydon, Surrey CR9 3QL, England).

The overall weight of a tablet according to the invention is variable,such as from approximately 50 to 2500 mg, more preferably 50 to 2000 mg,more preferably still 50 to 1500 mg, more preferably still 50 to 1200mg. The amount of swellable clay can vary over a large % w/w.

Thus for a dispersible tablet according to the present invention, theintra-granular amount of swellable clay such as a crystalline mineralclay for example, magnesium aluminium silicate is suitably present inthe following general ranges 0.25 to 60% w/w, preferably 0.25 to 50%w/w, more preferably 0.5 to 50% w/w, more preferably still 1 to 50% w/w,more preferably still 1 to 40% w/w, more preferably still 2 to 20% w/w,more preferably still 2.5 to 20% w/w, still more preferably 3 to 10%w/w, and most preferably 5 to 10%, most desirably about 5% w/w.

The tablets according to the invention will generally contain apre-determined amount of AMTP depending on the desired dosage and thetotal weight of the tablet.

In general tablets according to the invention should contain from 5 to95% w/w of AMTP, preferably 20 to 95% w/w, more preferably 50-95%, stillmore preferably 65-95%, still more preferably 65 to 85% w/w, and mostpreferably 70 to 85% w/w of AMTP.

Preliminary research shows that tablets of the invention will containfrom 50 to 800 mg of AMTP, such as unit tablet dosages containing anequivalent (unfactorized) amount of about 50 mg, about 100 mg, about 200mg, about 400 mg or about 800 mg of AMTP.

Based on our research, it has been found that when AMTP is present in anamount of at least 60% w/w in tablets according to the invention, wehave suprisingly found that the dispersion time remains substantiallyconstant over a range of tablet hardnesses. This is a considerablequality control advantage since in industrial manufacture it isessential to maintain a constant tablet hardness. Tablets according tothe invention can thus be produced with sufficient hardness andfriability so that they can easily be film-coated. A tablet according tothe invention should desirably have a friability of about 2% or less,preferably 0.5% or less.

According to a further embodiment of the present invention AMTP ispresent in an amount of 15 to 50%, preferably 15% to 25% w/w or 35% to45% w/w, for example in tablets containing respectively 25 mg and 50 mgof AMTP.

Based on experiments that we have carried out, it has been found that inaddition to the amount of swellable clay present within the granules ofthe tablet, a further amount of swellable clay may be present outsidethe granules. At very low intra-granular amounts (such as 1% w/w orbelow) of a swellable clay, higher extra-granular amounts (such as about10% w/w or more) of such clay may decrease the dispersion time, but ingeneral extra-granular addition has little or no effect on thedispersion time. The maximum percentage(s) of the clay present withinthe granules and, optionally outside the granules, may be limited byother practical considerations such as poor flow and compressionproperties.

In addition to the swellable clay disintegrating agent, the tabletsaccording to some aspects of the invention contain a furtherdisintegrating agent. Examples of such disintegrating agents which maybe employed in the tablets include the following agents:microcrystalline cellulose (e.g. Avicel R) 0 to 30% w/w, preferably 5 to10% w/w, Sodium carboxymethyl cellulose (e.g. Nymcel R) 0 to 5% w/w,preferably 1 to 2% w/w, calcium carboxymethyl cellulose 0 to 20% w/w,preferably 1 to 5% w/w, modified cellulose gum (e.g. Ac-Di-Sol R) 0 to10% w/w, preferably 1 to 5% w/w, cross-linked povidone 0 to 10% w/w,preferably 2 to 6% w/w, alginic acid and alginates 0 to 10% w/w, 2 to 5%w/w, pregelatinised starch 0 to 10% w/w, preferably 0.5 to 5% w/w,sodium starch glycollate (e.g. Explotab R, Primojel R) 0 to 10% w/w,preferably 0.5 to 5% w/w, modified corn starch (e.g. starch 1500 R) 0 to20% w/w, preferably 1 to 10% w/w, starch (e.g. potato/maize starch ) 0to 15% w/w, preferably 0.2 to 10% w/w, ion exchange resin such aspolacrin potassium (e.g. Amberlite IRP-88) up to 5% w/w, preferably 0.5to 2.0% w/w.

Experiments also indicate that if low-substituted hydroxypropylcellulose (LHPC) is used a suitable dispersion can be obtained withoutthe need for a separate wetting agent/surfactant.

According to a further embodiment of the invention, particularlypreferred further disintegrating agents for use in the tablets accordingto the invention include sodium starch glycollate (commerciallyavailable as Explotab), LHPC, low substituted hydroxypropylmethylcellulose (LHPMC) or a mixture of two or three thereof.

According to a further embodiment of the invention, the furtherdisintegrating agent is employed in an mount of 1 to 5% w/w.

In addition to the disintegrating agents referred to above, it will beappreciated that the tablet according to the invention may contain otherexcipients conventionally used in tablet manufacture including thefollowing:

Binders and Adhesives: we have found with some AMTP tablet formulationsthat if there is sufficient mount of swellable clay such as Veegum Fpresent within the granules, then a separate binder is not required(i.e. the clay also acts as a binder). Preferably however a separatebinder is present in a sufficient mount to provide a tablet having asatisfactory tablet hardness and satisfactory dispersion characterstics.The amount of binder will vary depending on the overall tabletformulation and type of binder used but general functional limits formost tablets of the invention are 0 to 25% w/w. The following bindersand mounts are suitable for inclusion in a tablet according to theinvention. The concentration of the binder in the granulation fluid (%w/v) is given (% w/w in tablet will vary according to the volume ofgranulating solution used to form a satisfactory tablet): Examples ofbinders are: acacia mucilage 0 to 25% w/v, preferably 1 to 5% w/v,alginic acid 0 to 20.0% w/v, preferably 1 to 5% w/v,polyvinylpyrrolidone (povidone) 0 to 15.0% w/v, preferably 0.5 to 5%w/v, gelatin 0 to 20.0% w/v, preferably 1 to 5.0% w/v, sucrose 0 to70.0% w/v, preferably 2.0 to 20.0% w/v, starch mucilage 0 to 10.0% w/v,preferably 0.5 to 5.0% w/v, pregelatinised starch 0 to 10.0% w/v,preferably 0.5 to 5.0% w/v, starch paste 0 to 10.0% w/v, preferably 5.0to 10.0% w/v, sodium alginate 0 to 5.0% w/v, preferably 1.0 to 3.0% w/v,sorbitol 0 to 10.0% w/v, preferably 3.0 to 10.0% w/v, tragacanth 0 to20% w/v, preferably 5.0 to 10.0% w/v, glucose 0 to 50%, preferably 5 to25% w/v, hydroxypropylmethyl cellulose (HPMC) 0 to 10% w/v, preferably1.0 to 5.0% w/v, magnesium aluminium silicate 0 to 40% w/v, preferably 2to 10% w/v, starch paste 0 to 25% w/v, preferably 5 to 15% w/v,polyvinylpyrrolidone 0 to 15% w/v, preferably 3 to 10% w/v,carboxymethylcellulose sodium 0 to 10% w/v, preferably 1 to 6% w/v,dextrin 0 to 50% w/v, preferably 5 to 25% w/v, ethyl cellulose 0 to 10%w/v, preferably 1 to 6% w/v, polyethylene glycol 0 to 5% w/v, guar gum 0to 10% w/v, preferably 1 to 5% w/v, zein 0 to 30% w/v, preferably 1 to10% w/v, hydroxyethyl cellulose 0 to 5% w/v, preferably 2 to 4% w/v,hydroxypropyl cellulose up to 5% w/v, preferably 2 to 4% w/v, methylcellulose up to 20% w/v, preferably 1 to 10% w/v, polymethacrylates upto 25% w/v, preferably 5 to 10% w/v, carboxymethylcellulose calcium 0 to20% w/v, preferably 5 to 10% w/v.

b) Fillers: These serve the purpose of bulking up the tablet to asuitable size and aiding compressibility especially in lower dosagetablets. The amount of filler depends on its type, size of tablet andamount of active compound. When the concentration of active compound isbelow 60% w/w, more preferably 45% w/w and most preferably below 30%w/w, an inorganic water-insoluble filler is advantageously used.Examples of water-soluble fillers (which can be used in generalquantifies of 0 to 95% w/w) are: soluble lactose, compressible sugar,confectioners sugar, dextrose, mannitol, sodium chloride, sorbitol,xylitol, sodium chloride F. Examples of water-insoluble fillers (whichcan be used in general quantities of 0 to 93% w/w) are: calciumcarbonate, magnesium carbonate, calcium phosphate (e.g. di and tri basiccalcium phosphate), calcium sulphate, kaolin, microcrystallinecellulose, powdered cellulose, pregelatinized starch 5 to 75%, starch,barium sulphate, magnesium trisilicate, aluminium hydroxide.

Inclusion of a filler having a negative heat of solution in water, forexample mannitol, sorbitol and xylitol, provides tablets which, inaddition to being water-dispersible, are especially suitable for chewingin the mouth, the dissolving of such an excipient in the salivaproducing a cool, pleasant sensation.

According to a further embodiment of the invention, particularlypreferred fillers for use in the tablets according to the inventioninclude lactose and more preferably calcium carbonate. Such fillers aregenerally employed in an amount of 20 to 80% for example 25 to 60% w/w,preferably 30 to 50 % w/w.

c) Lubricants: Examples of lubricants with percentage weights which aresuitable for a tablet are: stearates (e.g. magnesium or calciumstearate) 0.2 to 5% w/w, preferably 0.25 to 1% w/w, talc 0.19 to 5% w/w,preferably 1 to 2% w/w, polyethylene glycol 0.19 to 5% w/w, preferably 2to 5% w/w, liquid paraffin 0.18 to 5% w/w, preferably 2 to 5% w/w,sodium lauryl sulphate 0.19 to 5% w/w, preferably 0.5 to 2% w/w,magnesium lauryl sulphate 0.12 to 5% w/w, preferably 1 to 2% w/w,colloidal silicon dioxide 0.1 to 5% w/w, preferably 0.1 to 1.0% w/w,palmitostearate 0.01 to 5% w/w, preferably 1 to 3% w/w, stearic acid0.01 to 5% w/w, preferably 1 to 3% w/w, zinc stearate 0.01 to 2% w/w,0.5 to 1.5% w/w, hydrogenated vegetable oil 0.5 to 5% w/w, preferably 1to 3% w/w. More suitably the lower value is 0.25%.

d) Wetting agents/surfactants: examples with suitable mounts are: sodiumdodecyl sulphate 0 to 10% w/w, preferably 0.5 to 2% w/w, sodium laurylsulphate 0 to 10% w/w, preferably 0.1 to 3.0% w/w, polyoxyethylenesorbitan fatty acid esters (Tweens) 0 to 3% w/w, preferably 0.05 to 1.0%w/w, polyoxyethylene stearates 0 to 2% w/w, preferably 0.05 to 1.0% w/w,sorbitan fatty acid esters (Spans) 0 to 3% w/w, preferably 0.05 to 1.0%w/w.

e) Glidants: for example, talc 0 to 5% w/w, preferably 1 to 2% w/w,starch 0 to 15% w/w, preferably 2 to 10% w/w, magnesium stearate up to5%, preferably 0-2.0% w/w, silica derivatives generally 0 to 1% w/w,preferably 0.2 to 0.5% w/w, such as colloidal silica (e.g. Aerosil) 0 to0-5% w/w, preferably 0.25 to 3% w/w, pyrogenic silica 0 to 2% w/w,preferably 0.25 to 1% w/w, hydrated sodium silicoaluminate 0 to 2% w/w,preferably 0.5 to 1% w/w, colloidal silicon dioxide 0 to 0.5% w/w.

f) Flavouring agents: are used in for example approximate quantifies of0 to 5% w/w, preferably 0.25 to 2% w/w, orange, cherry and strawberry,raspberry, grape and passion fruit.

g) Sweetening agents: for example sodium saccharin 0 to 10% w/w,preferably, 0.5 to 5.0% w/w, aspartame 0 to 10% w/w, preferably 0.25 to5.0% w/w, confectioners sugar 0 to 30% w/w, preferably 5 to 20% w/w,sorbitol 25 to 90% w/w, preferably 0.5 to 10% w/w, sucrose 0 to 85% w/w,preferably 0.5 to 20% w/w, xylitol 0-20% w/w, preferably 0.5 to 10% w/w.

Such materials may be incorporated at the appropriate stage(s) of themanufacturing process together with any other agents (e.g. colourants).

A further aspect of present invention provides a process for thepreparation of a water-dispersible tablet comprising AMTP, together witha pharmaceutically acceptable swellable clay disintegrating agent whichcomprises bringing AMTP into association with the said swellable clay inthe formation of tablet granules to provide a water-dispersible tabletwhich is capable of dispersing in water within a period of 3 minutes toprovide a dispersion which is capable of passing through a sieve screenwith a mesh aperture of 710 μm in accordance with the test fordispersible tablets defined in the British Pharmacopoeia, 1988, Volume11, page 895.

The present invention further provides a process for the preparation ofa water-dispersible tablet comprising AMTP, together with apharmaceutically acceptable swellable clay disintegrating agent and afurther disintegrating agent which comprises bringing AMTP intoassociation with the said swellable clay and further disintegratingagent in the formation of the tablet granules to provide awater-dispersible tablet which is capable of dispersing in water withina period of 3 minutes to provide a dispersion which is capable ofpassing through a sieve screen with a mesh aperture of 710 μm inaccordance with the test for dispersible tablets defined in the BritishPharmacopoeia, 1988, Volume 11, page 895. Preferably said processcomprises the steps of:

a) admixing in dry, finely-divided form AMTP with an effective mount ofa pharmaceutically acceptable swellable clay and a furtherdisintegrating agent, optionally with the addition of one or more otherpharmaceutical carriers or excipients;

b) addition of a quantity of a pharmaceutically acceptable liquidsufficient to moisten the dry mixture;

c) granulation of the resulting moist mixture to form granules;

d) drying the granules and optionally blending the granules with otheroptional carriers or excipients such as lubricants, glidants, flavouringagents and disintegrating agents; and

e) compression of the granules to form a tablet which is capable ofdispersing in water within a period of 3 minutes to provide a dispersionwhich is capable of passing through a sieve screen with a mesh apertureof 710 μm in accordance with the above defined British Pharmacopoeiatest for dispersible tablets.

Other aspects of the tablet preparation will now be discussed.

Suitably the dry mixing is effected with a mixing time of 5 minutes to25 minutes preferably about 10 minutes.

The swellable clay can be dry mixed with AMTP and other excipients andthen granulating solution added, or the clay and other excipients can bedispersed firstly in the granulating solution and then added to the AMTPand any other excipients prior to granulation.

The liquid employed to moisten the dry mixture, prior to the granulationstep, is preferably aqueous, for example water or a mixture of water anda suitable alcohol such as ethanol or isopropanol.

Wet mixing or granulating times which are suitable (depending on thetype of mixer used) are 5 to 20 minutes.

Suitable granule drying times and conditions (which will vary accordingto the type of equipment used and batch size of granules) are about 50°to 80° C., (using a dryer such as with a tray or fluid bed dryer) toobtain a moisture content generally below about 4%.

The tablets may optionally be film-coated, for example withhydroxypropylmethyl cellulose, polyethylene glycol or titanium dioxide,and/or may be scored and/or may be polished, for example withpolyethylene glycol 8000. If the tablets are film-coated, this makesthem easier to swallow or chew (i.e. the tablets are suitable for eitherdispersion in water or for direct swallowing or chewing), but thedispersion time is increased.

Tablets according to the invention containing AMTP advantageouslyinclude a magnesium aluminium silicate such as Veegum F as the swellableclay optionally together with further pharmaceutical carriers orexcipients referred to above such as disintegrating agents, binders,fillers, lubricants etc.

According to one embodiment of the invention, a formulation of an AMTPdispersible tablet containing from 50 mg-800 mg AMTP comprises:

    ______________________________________                                        AMTP       65% w/w to 95% w/w, preferably 70-85% w/w                          Povidone   0.25% w/w to 5% w/w, preferably 0.5-2% w/w                         Magnesium  0.5% w/w to 30% w/w, preferably 0.5-10% w/w                        aluminium                                                                     silicate                                                                      Veegum F or                                                                   bentonite                                                                     Microcrystaliine                                                                         5% w/w to 25% w/w, preferably 5-15% w/w                            cellulose                                                                     Avicel PH101                                                                  or LHPC-LH11                                                                  Sodium starch                                                                            0% w/w to 8% w/w, preferably 1-25% w/w                             glycollate                                                                    Magnesium  0.25% w/w to 2% w/w, preferably 0.25-1.0% w/w                      stearate                                                                      and if optionally                                                             film coated:                                                                  Opadry     0.1% w/w to 2% w/w, preferably 0.25-1.0% w/w                       Polyethylene                                                                             0.1% w/w to 0.5% w/w, preferably 0.1-0.2% w/w                      glycol 8000                                                                   ______________________________________                                    

According to a further embodiment of the invention, a formulation of anAMTP dispersible tablet comprises AMTP, preferably in an mount of 30 to50% w/w, preferably 35 to 45% w/w and further including one or moreingredients and proportions thereof each selected independently from thefollowing:

    ______________________________________                                        AMTP      15% w/w to 50% w/w, preferably 45-45%                               Calcium Carbo-                                                                          25% w/w to 60% w/w, preferably 30-50% w/w                           nate                                                                          LHPC or   5% w/w to 30% w/w, preferably 5-15% w/w                             LHPMC or                                                                      Microcrystalline                                                              cellulose (e.g.                                                               Avicel PH101)                                                                 Veegum F or                                                                             0.25% w/w to 30% w/w, preferably 2-8% w/w                           bentonite or                                                                  attapulgite                                                                   Povidone  0.25% w/w to 5% w/w, preferably 0.5-2% w/w                          (e.g. PVP k30)                                                                Sodium starch                                                                           1% w/w to 8% w/w, preferably 1-5% w/w glycollate                    Magnesium 0.25% w/w to 2% w/w, preferably 0.25-1.0% w/w                       stearate                                                                      and if optionally                                                             film coated:                                                                  Opadry    0.1% w/w to 2% w/w, preferably 0.25-1.0% w/w                        Polyethylene                                                                            0.1% w/w to 0.5% w/w, preferably 0.1-0.2% w/w                       glycol 8000                                                                   ______________________________________                                    

The water-dispersible tablets of AMTP according to the invention may beused to treat or prevent neurodegenerative and other neurologicaldisorders of the central nervous system the aetiology of which includesexcessive release of neurotransmatter glutamate, including Alzheimer'sdisease, cerebral ischaemic damage, chronic pain and epilepsy, AMTP inthe above tablets may be administered in the dosages generally disclosedin European Patent Specification No. 372934, more preferably 1 to 10mg/kg/day. Such dosages may be provided for example by theadministration of a 25 mg or 50 mg tablet.

The following Examples illustrate the present invention.

    ______________________________________                                        Example 1        2        3      4      5                                     Number  mg/tablet                                                                              mg/tablet                                                                              mg/tablet                                                                            mg/tablet                                                                            mg/tablet                             ______________________________________                                        AMTP*   50.0     100.0    200.0  400.0  800.0                                 LHPC-LH11                                                                             6.0      12.0     24.0   48.0   96.0                                  Veegum F                                                                              3.2      6.4      12.8   25.6   51.2                                  PVP K30 0.7      1.4      2.8    5.6    11.2                                  Explotab                                                                              2.0      4.0      8.0    16.0   32.0                                  Mg Stearate                                                                           0.6      1.2      2.4    4.8    9.6                                   tab weight                                                                            62.5 mg  125.0 mg 250.0 mg                                                                             500.0 mg                                                                             1000.0 mg                             tab diam                                                                              5.6      7.4      8.6    11.0   14.0                                  (mm)                                                                          tab hardness                                                                          2.0      4.0      6.0    10.0   14.0                                  ______________________________________                                        Example 6        7                                                            Number  mg/tablet                                                                              mg/tablet                                                    ______________________________________                                        AMTP*   100.0    200.0                                                        LHPC-LH11                                                                             14.0     28.0                                                         Veegum F                                                                              7.0      14.0                                                         Calcium 12.0     24.0                                                         Carbonate                                                                     PVP K30 2.0      4.0                                                          Explotab                                                                              4.0      8.0                                                          Mg Stearate                                                                           1.0      2.0                                                          tab weight                                                                            140.0 mg 280.0 mg                                                     (mg)                                                                          tab hardness                                                                          6.0 kg   8.0 kg                                                       tab diam                                                                              7.4 mm   8.6 mm                                                       ______________________________________                                         *unfactorized value                                                      

Method of Preparation

The tablets described in Examples 1-7 above were prepared according tothe following general method:

(a) A dry mixture was made of all components except Povidone/PVP K30,sodium docusate (if present) and magnesium stearate;

(b) The Povidone/PVP K30 and sodium docusate (if present) were dissolvedin 50% aqueous alcohol to form a granulation solution;

(c) The granulation solution was added to the dry mixture to formgranules;

(d) The wet granules were dried in a fluid bed dryer;

(e) The granules were then sifted through a 1000 μm diameter mesh sieve;and

(f) The dried granules were blended with the magnesium stearate andcompressed to form tablets.

Flavouring agents where present were added at blending step (f) above.

This general method is illustrated with respect to the followingspecific examples.

EXAMPLES 1 TO 7 Uncoated Tablets

(a) A dry mixture was made of all components except Povidone/PVP K30 andmagnesium stearate using a Diosna P100 (high shear mixer--granulator)for 3 minutes.

(b) The Povidone/PVP K30 was dissolved in 50% aqueous alcohol to form agranulation solution.

(c) The granulation solution was added to an approximate quantity of 300ml per kg dry weight to the dry mixture to form granules. Wet mixing wascarried out for approximately 5 minutes.

(d) The wet granules were dried in an Aeromatic T3 fluid bed drier at atemperature of 70° C. for approximately 30 minutes. The moisture contentof the granules was approximately 4%.

(e) The granules were then sifted through a 1000 μm diameter mesh sieveusing a Jackson Crockatt No.7 sifter.

(f) The dried granules were blended with the magnesium stearate using acollette mixer for approximately 10 minutes and compressed to formtablets using a Manesty D3 Rotary tablet press fitted with caplet shapedpunches of approximately 19.3 mm length and 9.0 mm breadth. Tablets werecompressed to a weight of 1052 mg±2%.

This granule can be used to make other strengths of AMTP dispersibletablets. If gum coated tablets were required, they could be made asfollows:

Steps (a) to (f) described hereabove would be repeated to form anuncoated tablet which was then film-coated by the following procedure.

The film-coating apparatus used was a Manesty Accellacota 10. Thecoating suspension was sprayed onto the tablet cores to a target weightincrease of between 0.5-1.0% using suitable parameters of:

pan rotation speed (8.5 rpm)

spray (application rate (˜20 g per min)

inlet temperature (˜75° C.)

exhaust temperature (˜53° C.).

A polish coat of PEG8000 was then applied to the film-coated tablets, toa further weight gain of 0.1-0.2%.

The tablets prepared in accordance with the above Examples were thentested as follows.

Tablet Evaluation Methods

1. Average tablet weight. Twenty tablets were weighed on an analyticalbalance and the average tablet weight calculated.

2. Tablet breaking strength (kilo pond-kp). 5 tablets were individuallytested using a Schleuniger crashing strength tester, and the averagebreaking strength calculated.

3. Friability (% loss). 10 tablets, accurately weighed, were subjectedto 10 minutes friability testing using a Roche Friabilator. The tabletswere dedusted, reweighed, and the weight loss due to the friability wascalculated as a percentage of the initial weight.

4. Dispersion Disintegration time DT (BP 1988). 6 tablets were tested inaccordance to the above-defined BP test (without discs) for dispersibletablets. This utilises water at a temperature of 19°-21° C.

5. Dispersion Quality. In accordance with the BP uniformity ofdispersion test for dispersible tablets (BP 1988 Volume II page 895),two tablets were placed in 100 ml of water at 19°-21° C. and allowed todisperse. A smooth dispersion was produced which passed through a 710 μmmesh sieve.

Granule Evaluation Methods

1. Loss on Drying (LOD). The residual moisture content of the granule(LOD) is determined on a 3-4 g sample using a Computrac moistureanalyser set to 90° C. operated in accordance with the manufacturer'sprocedure.

2. Weight Median Diameter (WMD). A 10 g sample of granule is sifted for2 minutes at suitable pulse and sift amplitudes in an Allen Bradleysonic sifter in accordance with manufacturer's instructions. Sieves of710 μm, 500 μm, 355 μm, 250 μm, 150 μm, 106 μm and 53 μm were used. TheWMD is calculated from the cumulative percentage undersize sizedistribution using a computer programme.

A particle size analysis is carried out on the dispersion of a tablet ofthe invention in accordance with the following method.

The particle size distribution can be determined using a Malvern 2600particle analyser as follows. The instrument was set to analyseparticles in liquid with magnetic stirrer fitted. A 300 mm focal lengthlens may be used.

1. Disperse tablet in 100 ml of de-ionised water.

2. Agitate solution for approximately 2 hours.

3. Filter or centrifuge solution to obtain liquor which should besaturated with all ingredients present in the tablet.

4. Disperse second tablet in 50 ml of saturated liquor allowing 3minutes to fully disperse. Agitate vigorously and remove a sample of thedispersion within 5 minutes adding sufficient quantity to the MalvernPIL cell containing the liquor to obtain an observation value of0.15-0.30. Analyse sample.

Further examples of tablets according to the invention are describedbelow:

    __________________________________________________________________________    Example    8        9        10                                               Number     mg/tablet                                                                          %/tablet                                                                          mg/tablet                                                                          %/tablet                                                                          mg/tablet                                                                          %/tablet                                    __________________________________________________________________________    AMTP       50   40  50   40  50   40                                          Lactose    50   40  34.5 27.6                                                                              16.2 13                                          Calcium carbonate            32.4 25.9                                        Avicel              15   12                                                   LHPC I1    12   9.6 12   9.6 12   9.6                                         Veegum     6.4  5.1 7    5.6 7    5.6                                         Explotab   4    3.2 4    3.2 4    3.2                                         Povidone   1.4  1.1 1.5  1.2 2.5  2                                           Magnesium stearate                                                                       1.2  1   1    0.8 1    0.8                                         __________________________________________________________________________    Example    11       12       13       14                                      Number     mg/tablet                                                                          %/tablet                                                                          mg/tablet                                                                          %/tablet                                                                          mg/tablet                                                                          %/tablet                                                                          mg/tablet                                                                          %/tablet                           __________________________________________________________________________    AMTP       50   40  100  40  500  40  50   40                                 Calcium carbonate                                                                        49.5 39.6                                                                              97   38.8                                                                              51.8 41.4                                                                              48.4 38.7                               LHPC 11    12   9.6 24   9.6 12   9.6 12   9.6                                Veegum     7    5.6 14   5.6 3.8  3   7    5.6                                Explotab   4    3.2 8    3.2 4    3.2 4    3.2                                Povidone   1.5  1.2 5    2   2.5  2   2.5  2                                  Magnesium stearate                                                                       1    0.8 2    0.8 1    0.8 1    0.8                                Sodium Lauryl Sulphate                0.13 0.1                                __________________________________________________________________________

The tablets defined in Examples 8 to 14 were prepared in accordance withthe general method of preparation described above for Examples 1 to 7.

The tablets defined in Examples 8 to 14 were tested in accordance withthe procedures described above with the following results:

    ______________________________________                                                                        DISPERSION                                                                    DISINTEGRATION                                          DIE SIZE   HARDNESS   TIME                                          EXAMPLE   (mm)       (kp)       (seconds)                                     ______________________________________                                        8         7.4        2.8        65-90                                                              4.4        90-107                                                             max 6      90-105                                        9         7.4        5          50-68                                                              8          247-257                                                            max 13                                                   10        7.4        3.2        81-96                                                              7          248-265                                                            max 10     --                                            11        8.6        5.8        18-23                                                              9.1        34-39                                                              max 10     --                                            12        7.4        6.4        28-32                                                              9.8        45-55                                                              max 15.4   110-130                                       13        7.4        3.4        19-23                                                              7.1        105-118                                                            max 11.3   265-270                                       14        7.4        3.2        33-35                                                              6.8        45-49                                                              9.1        60-66                                         ______________________________________                                    

We claim:
 1. A water-dispersible tablet comprising within the granulesof the tablet4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidinetogether with a pharmaceutically acceptable swellable claydisintegrating agent and a further pharmaceutically acceptabledisintegrating agent; and outside the granules, lubricant; to provide atablet which is capable of dispersing in water within a period of 3minutes to provide a dispersion which is capable of passing through asieve screen with a mesh aperture of 710 μm in accordance with the testfor dispersible tables defined in the British Pharmacopoeia, 1988,Volume II, page
 895. 2. A tablet as claimed in claim 1 containing 15 to50% w/w of4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine.3. A tablet as claimed in claim 1 or claim 2 in which the swellable clayis a magnesium aluminium silicate.
 4. A tablet as claimed in any of thepreceding claims containing 3 to 10% w/w of the swellable clay.
 5. Atablet as claimed in any of the preceding claims in which the furtherdisintegrating agent is selected from sodium starch glycollate, lowhydroxypropyl cellulose (LHPC) and low hydroxypropylmethylcellulose(LHPMC).
 6. A tablet as claimed in any of the preceding claimscontaining 1 to 5% w/w of the further disintegrating agent.
 7. A tabletas claimed in any of the preceding claims containing a filler.
 8. Atablet as claimed in claim 7 in which the filler is calcium carbonate.9. A tablet as claimed in claim 7 or claim 8 containing 25 to 60% w/w ofthe filler.
 10. A tablet as claimed in any of the preceding claimscontaining a povidone binder.
 11. A process for the preparation of awater-dispersible tablet comprising within the granules of the tablet4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine("AMTP"), together with a pharmaceutically acceptable swellable claydisintegrating agent and a further disintegrating agent and outside thegranules, lubricant, which process comprises bringing AMTP intoassociation with the swellable clay and further disintegrating agent inthe formation of tablet granules and blending the granules withlubricant and optionally other carrier or excipients to provide awater-dispersible tablet which is capable of dispersing in water withina period of 3 minutes to provide a dispersion which is capable ofpassing through a sieve screen with a mesh aperture of 710 μm inaccordance with the test for dispersible tablets defined in the BritishPharmacopoeia, 1988, Volume II, page
 895. 12. A water-dispersible tabletas claimed in any of claims 1 to 10 for the treatment or preparation ofneurodegenerative or other neurological disorders of the central nervoussystem, the aetiology of which includes excessive release ofneurotransmitter glutamate.
 13. A water-dispersible tablet comprisingwithin the granules of the tablet AMTP together with a pharmaceuticallyacceptable swellable clay disintegrating agent and outside the granules,lubricant; to provide a tablet which is capable of dispensing in waterwithin a period of 3 minutes to provide a dispersion which is capable ofpassing through a sieve screen with a mesh aperture of 710 μm inaccordance with the test for dispersible tablets defined in the BritishPharmacopoeia, 1988, Volume II, page 895.